Shortening time for access to alcohol drives up front-loading behavior, bringing consumption in male rats to the level of females

Background Incentives to promote drinking (“happy hour”) can encourage faster rates of alcohol consumption, especially in women. Sex differences in drinking dynamics may underlie differential health vulnerabilities relating to alcohol in women versus men. Herein, we used operant procedures to model the happy hour effect and gain insight into the alcohol drinking dynamics of male and female rats. Methods Adult male and female Wistar rats underwent operant training to promote voluntary drinking of 10% (w/v) alcohol (8 rats/sex). We tested how drinking patterns changed after manipulating the effort required for alcohol (fixed ratio, FR), as well as the length of time in which rats had access to alcohol (self-administration session length). Rats were tested twice within the 12 h of the dark cycle, first at 2 h (early phase of the dark cycle, “early sessions”) and then again at 10 h into the dark cycle (late phase of the dark cycle, “late sessions”) with an 8-h break between the two sessions in the home cage. Results Adult females consumed significantly more alcohol (g/kg) than males in the 30-min sessions with the FR1 schedule of reinforcement when tested late in the dark cycle. Front-loading of alcohol was the primary factor driving higher consumption in females. Changing the schedule of reinforcement from FR1 to FR3 reduced total consumption. Notably, this manipulation had minimal effect on front-loading behavior in females, whereas front-loading behavior was significantly reduced in males when more effort was required to access alcohol. Compressing drinking access to 15 min to model a happy hour drove up front-loading behavior, generating alcohol drinking patterns in males that were similar to patterns in females (faster drinking and higher intake). Conclusions This strategy could be useful for exploring sex differences in the neural mechanisms underlying alcohol drinking and related health vulnerabilities. Our findings also highlight the importance of the time of testing for detecting sex differences in drinking behavior.

Activation of G protein-coupled estradiol receptor 1 in the dorsolateral striatum enhances motivation for cocaine and drug-induced reinstatement in female but not male rats

Background Estradiol potentiates drug-taking behaviors, including motivation to self-administer cocaine and reinstatement of drug-seeking after extinction in females, but not males. The dorsolateral stratum (DLS) is a region of the brain implicated in mediating drug-seeking behaviors and, more specifically, is a target brain area to study how estradiol regulates these behaviors. The estradiol receptors α, β, and G protein-coupled estradiol receptor 1 (GPER1) are all present in the DLS. In this study, the effects of activating GPER1 in the DLS on drug-seeking are investigated. Methods Gonad-intact male and female rats were trained to self-administer cocaine (0.4 mg/kg/inf) on a fixed-ratio 1 schedule of reinforcement. For 4 weeks, animals underwent testing on a progressive ratio schedule of reinforcement to determine their motivation to attain cocaine. Halfway through progressive ratio testing, a selective agonist targeting GPER1 (G1) was administered intra-DLS to determine the contribution of GPER1 activation on motivation for cocaine. The effects of intra-DLS GPER1 activation on drug-induced reinstatement after extinction were subsequently determined. Results Activation of GPER1, via intra-DLS G1 administration, potentiated females’ motivation to self-administer cocaine. There was no effect of prior G1 treatment on extinction of cocaine-taking in females; however, G1 treatment resulted in greater drug-induced reinstatement (10 mg/kg cocaine, i.p.). There were no effects of intra-DLS GPER1 activation observed on motivation for cocaine or cocaine-induced reinstatement of responding in males. Conclusions These results support the conclusion that activation of GPER1 in the DLS enhances cocaine-seeking behaviors for female, but not male rats.

Activation of G-protein Coupled Estradiol Receptor 1 in the Dorsolateral Striatum Enhances Motivation for Cocaine and Drug-Induced Reinstatement in Female Rats

BackgroundEstradiol potentiates drug-taking behaviors, including motivation to self-administer cocaine and reinstatement of drug-seeking after extinction in females, but not males. The dorsolateral stratum (DLS) is a region of the brain implicated in mediating drug-seeking behaviors and more specifically, is a target brain area to study how estradiol regulates these behaviors. The estradiol receptors α, β, and G-protein coupled estradiol receptor 1 (GPER1) are all present in the DLS. In this study the effects of activating GPER1 in the DLS on drug-seeking are investigated. MethodsGonad-intact male and female rats were trained to self-administer cocaine (0.4 mg/kg/inf) on an fixed-ratio 1 schedule of reinforcement. For four weeks, animals underwent testing on a progressive ratio schedule of reinforcement to determine their motivation to attain cocaine. Halfway through progressive ratio testing, a selective agonist targeting GPER1 (G1) was administered intra-DLS to determine the contribution of GPER1 activation on motivation for cocaine. The effects of intra-GPER1 activation on drug-induced reinstatement after extinction was subsequently determined. ResultsActivation of GPER1, via G1 administration intra-DLS potentiated females’ motivation to self-administer cocaine. There was no effect of prior G1 treatment on extinction of cocaine-taking in females, however, G1 treatment resulted in greater drug-induced reinstatement (10 mg/kg cocaine, i.p.). There were no effects of intra-DLS GPER1 activation observed on motivation for cocaine or cocaine-induced reinstatement of responding in males. Conclusions These results support the conclusion that activation of GPER1 in the DLS enhances cocaine seeking behaviors for female, but not male rats.

Caffeine Increases the Reinforcing Efficacy of Alcohol, an Effect that is Independent of Dopamine D2 Receptor Function

The rising popularity of alcohol mixed with energy drinks (AmEDs) has become a significant public health concern, with AmED users reporting higher levels of alcohol intake than non-AmED users. One mechanism proposed to explain heightened levels of alcohol intake in AmED users is that the high levels of caffeine found in energy drinks may increase the reinforcing properties of alcohol, an effect which may be dependent on interactions between adenosine signaling pathways and the dopamine D2 receptor. Therefore, the purpose of the current study was to confirm whether caffeine increases the reinforcing efficacy of alcohol using both fixed ratio (FR) and progressive ratio (PR) designs, and to investigate a potential role of the dopamine D2 receptor in caffeine’s reinforcement-enhancing effects. Male Long Evans rats were trained to self-administer a sweetened alcohol or sucrose solution on an FR2 schedule of reinforcement. Pretreatment with caffeine (5-10 mg/kg) significantly increased operant responding for the sweetened alcohol reinforcer, but not sucrose. PR tests of motivation for alcohol or sucrose likewise confirmed a caffeine-dependent increase in motivation for a sweetened alcohol solution, but not sucrose. However, the D2 receptor antagonist eticlopride did not block the reinforcementenhancing effects of caffeine using either an FR or PR schedule of reinforcement. Taken together, these results support the hypothesis that caffeine increases the reinforcing efficacy of alcohol, which may explain caffeine-induced increases in alcohol intake. However, the reinforcement-enhancing effects of caffeine appear to be independent of D2 receptor function.